The present invention relates generally to methods of polymer preparation and, more specifically, to thiourea-containing dendrimer and thiourea-containing hyperbranched polymer as well as their preparation methods and applications.
Dendrimers are a class of artificial macromolecules with tree-like topological structures, synthesized by repeated growing basic reaction with characteristic of structural perfection, and highly molecular symmetry. Generally, the synthesis methods can be classified into divergent approach (Ihre H, Padilla De Jesús O L and Fréchet J M, Fast and convenient divergent synthesis of aliphatic ester dendrimers by anhydride coupling. Journal of the American Chemical Society 2001, 123: 5908-5917.) and convergent approach (Parrott M C, Benhabbour S R, Saab C et al., Synthesis, Radiolabeling, and Bio-imaging of High-Generation Polyester Dendrimers. Journal of the American Chemical Society 2009, 131: 2906-2916.). Employing highly-efficient reactions can increase dendrimer synthesis efficiency. For instance, CN101591428B is directed to an approach to the synthesis of polyester dendrimers, wherein the method greatly simplifies the preparation and purification process by taking advantages of two Michael additions, namely thiol-methacrylate reaction and amine-acrylate reaction. In addition, using the copper(I)-catalyzed azide alkyne cycloaddition and thiol-ene addition, Craig J. Hawker et al. synthesized a class of polyester dendrimers efficiently (Antoni P, Robb M J, Campos L et al., Pushing the Limits for Thiol-Ene and CuAAC Reactions: Synthesis of a 6th Generation Dendrimer in a Single Day. Macromolecules 2010, 43: 6625-6631.). However, up to now, none of them shows inherent therapeutic efficacy.
Isothiocyanate-amine coupling is a high-efficient reaction. The resulting thiourea moiety exhibits excellent biological activities including broad spectrum antimicrobial, bactericidal and antiviral effects (Liu J, Yang S, Li X et al., Synthesis and antiviral bioactivity of chiral thioureas containing leucine and phosphonate moieties. Molecules 2010, 15: 5112-5123.). For example, CN1138323 A is directed to a water-soluble anionic polythiourea with anti-human immunodeficiency virus and anti-AIDS-related complex effect. Moreover, some thiourea-compounds exhibited antitumor activity. (Manjula S, Malleshappa Noolvi N, Vipan Parihar K et al., Synthesis and antitumor activity of optically active thiourea and their 2-aminobenzothiazole derivatives: A novel class of anticancer agents. European Journal Of Medicinal Chemistry 2009, 44:2923-2929). But these compounds were all cytotoxic agents and their antitumor activity resulted from their cell-killing behavior. For example, during in vitro experiments, these compounds all can kill cancer cells and the concentration to kill 50% of cancer cells (IC50) is at micro mole level. Such cell-killing behavior makes cytotoxic agents also harmful to normal tissues, limiting the application of such thiourea compounds.